Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy

Mutations in enzymes involved in sphingolipid metabolism and trafficking cause a variety of neurological dis-orders, but details of the molecular pathophysiology remain obscure. SPTLC1 encodes one subunit of serinepalmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis. Mutations in SPTLC1 causehereditary sensory and autonomic neuropathy (type I) (HSAN1), an adult onset, autosomal dominant neuro-pathy. HSAN1 patients have reduced SPT activity. Expression of mutant SPTLC1 in yeast and mammalian cellcultures dominantly inhibits SPT activity. We created transgenic mouse lines that ubiquitously overexpresseither wild-type (SPTLC1